NIH GUIDE, Volume 25, Number 32, September 27, 1996


P.T. 34


  Gene Therapy+ 



National Heart, Lung, and Blood Institute


Annual Receipt Dates:  April 1, August 1, and December 1 for STTR

                       April 15, August 15, and December 15 for SBIR




The purpose of this notice is to emphasizes the importance of this

research topic to the National Heart, Lung, and Blood Institute

(NHLBI), National Institutes of Health (NIH).  Collaboration between

small business concerns and research institutions, including colleges

and universities, is encouraged to design and develop gene therapy

vectors and delivery systems for cardiovascular, pulmonary and

hematologic gene therapy.  Such collaboration is essential in order

to qualify for support under the Small Business Technology Transfer

(STTR) program and is permissible under the Small Business Innovation

Research (SBIR) program.


The "development of new gene therapy vectors and delivery systems" is

a research topic of special interest to the NHLBI, NIH, and is



subtopics NN and E.  It is identified also in the OMNIBUS


subtopics JJJ, BB, Q,and Y.


The solicitations are available electronically through the NIH,

Office of Extramural Research "Small Business Funding Opportunities"

Home Page located at:  In

addition, a limited number of hard copies of the solicitations have

been produced.  Subject to availability, they may be obtained from

the PHS STTR/SBIR Solicitation Office, phone (301) 206-9385; fax:

(301) 206-9722; e-mail:






Gene therapy or the introduction of genetic material into human cells

with successful expression of the inserted gene is a historic

technological advance.  It allows the development of novel strategies

for prevention, control, and treatment of disease through the use of

gene transfer.  However, gene therapy is still in its infancy and

faces many difficult biotechnical hurdles before it can achieve

widespread clinical application.


Somatic gene therapy entails two critical steps: delivery of the gene

to the appropriate cells and its subsequent maintenance and

expression.  In order to deliver the gene to the appropriate cell,

there must be a vehicle, or vector that will enter the cell and

transfer the genetic material into the host genome without adverse

effects.  To date, several vector systems such as RNA viruses

(retroviruses), DNA viruses (adenoviruses, adeno-associated viruses,

herpesviruses, and poxviruses), and naked or complexed DNA have been

developed.  However, none of these vectors are entirely satisfactory.


Presently, retroviruses and adenoviruses are the most extensively

employed vectors in clinical protocols.  However, both have

advantages and disadvantages.  Most retroviruses are efficient in

entering cells and integrating the transferred material into the host

genome but only if the cells are dividing.  In addition, their

preparation is cumbersome, titer yields are often low and they have a

limited carrying capacity for added genetic material.  On the other

hand, adenoviruses can enter dividing or nondividing cells, have high

titers and levels of expression, and relative ease of handling.

Their major drawback is that they may elicit immunogenic responses

from the host.  Experience with other DNA viral or nonviral systems

is less extensive and in its infancy.


Expanded and new research in collaboration with industry will enhance

the development of gene transfer technology.  Development of novel

vectors, modifications of existing vectors, and production of GMP-

grade vectors for clinical testing are areas particularly suited to

industry/academia collaborations.  Modern biotechnology and

pharmaceutical companies have important attributes: (1) skill in

translational research and the development of drug products; (2)

significant experience in meeting high manufacturing and quality

control standards; (3) professional staffs expert in regulatory and

clinical issues; and(4) high level of scientific and technical

expertise.  Involvement of industry in gene therapy technology will

facilitate the transfer of technology from the bench to the bedside

and bring products into the marketplace and into clinical practice at

the most rapid rate.


The potential of gene transfer to treat cardiovascular diseases is

substantial.  However, there are unique features of cardiovascular

diseases that require special gene transfer approaches.  For example,

the focal nature of coronary artery disease and restenosis may

require direct delivery of therapeutic genetic material to specific

myocardial or vascular sites.  Additional challenges encountered with

cardiovascular cells include the non-dividing nature of some cell

types, such as heart myocytes.  Strategies for other cardiovascular

diseases might include gene transfer to: treat myocardial ischemia by

promoting collateral circulation; modify vascular smooth muscle

contractility to reduce the total peripheral vascular resistance

observed to occur in hypertensive patients; and prevent cardiac

transplantation rejection by altering the cell surface properties to

deter an immune response.


There are many opportunities for application of gene transfer

techniques to prevention and treatment of pulmonary disorders.

Although there have been several promising advances in the use of

gene transfer approaches for cystic fibrosis, major barriers for this

and other pulmonary diseases to further progress exist.  Mechanisms

that underlie the immune response to viral vectors need to be

elucidated. The development and characterization of more efficient

gene transfer delivery systems need to be established.  The use of

gene transfer to ameliorate or prevent inflammatory lung disorders

such as ARDS and asthma is just beginning to be explored.  Gene

transfer to the pulmonary vasculature is also largely unexplored.

The role of this approach to treating pulmonary thrombosis, pulmonary

hypertension, or other conditions needs to be evaluated.

Bronchopulmonary dysplasia, pulmonary fibrosis, and chronic

obstructive pulmonary disease are other potential targets for the use

of gene transfer.


Many of the problems and needs relevant to gene transfer in the

cardiovascular and pulmonary areas are generally applicable to

hematologic genetic diseases such as hemophilia, sickle cell disease,

and thalassemia.  Choice of the appropriate target cell ranges from

important to critical for hematologic disorders.  In the case of

hemophilia, the normal site of production of factors VIII and IX is

believed to be the liver; however, other target cells such as

myoblasts and fibroblasts have been used in preliminary experiments.

Studies of mechanisms of development and suppression of immunity to

newly expressed gene products will also be an important issue.  Thus,

although much progress has been made, many basic issues crucial to

clinical success remain.




This program is open to all approaches for effective gene therapy

vector designs and delivery methods.  Research needs include, but are

not limited to, the following:


Gene Expression:  The transferred gene must be expressed in

sufficient amounts and in a physiologically correct manner.


Gene Delivery and Transfer:  Studies might involve viral, physical,

chemical and fusion techniques to develop improved packaging and more

effective gene delivery.  Recent developments in controlled drug

release technology, including the use of biodegradable polymers in

the form of layers or microspheres and containing the desired gene,

may be applicable to gene delivery.


Target Cells:  Appropriate target cell population for gene transfer

of cardiovascular, pulmonary, and hematologic diseases should be



Cellular and Humoral Immunity:  Interventions to suppress the immune

response are in need of exploration, as well as the development of

novel vector systems that selectively minimize or repress the immune

response of the host organism.


Model Systems:  Model systems (in vivo and in vitro) need to be

developed to assess the safety and efficacy of viral and nonviral

vector systems.




Eligibility requirements, definitions, application procedures, review

considerations, application forms and instructions, and other

pertinent information (including policy information, for example,

Inclusion of Women and Minorities in Research Involving Human

Subjects) are contained in the STTR and SBIR solicitations identified

in ~Purpose~ above.


Inquiries concerning this notice are encouraged. Direct inquiries

regarding programmatic issues to:


Sonia Skarlatos, Ph.D.

Division of Heart and Vascular Diseases

National Heart, Lung, and Blood Institute

6701 Rockledge Drive, Suite 10186, MSC 7956

Bethesda, MD  20892-7956

Telephone:  (301) 435-0550

FAX:  (301) 480-2848



Susan Banks-Schlegel, Ph.D.

Division of Lung Diseases

National Heart, Lung and Blood Diseases

6701 Rockledge Drive, Suite 10220, MSC 7952

Bethesda, MD  20892-7952

Telephone:  (301) 435-0202

FAX:  (301) 480-3557



Carol Letendre, Ph.D.

Division of Blood Diseases and Resources

National Heart, Lung and Blood Diseases

6701 Rockledge Drive, Room 10162, MSC 7950

Bethesda, MD  20892-7950

Telephone:  (301) 435-0080

FAX:  (301) 480-0867



Direct inquiries regarding fiscal matters to:


Ms. Marie Willett

Grants Operations Branch

National Heart, Lung, and Blood Institute

6701 Rockledge Drive, Suite 7128, MSC 7128

Bethesda, MD  20892-7128

Telephone:  (301) 435-0177

FAX:  (301) 480-3310




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